Inflammatory Bowel Disease (IBD) consists of two major types, namely Crohn's Disease (CD) and Ulcerative Colitis (UC). The number of new cases diagnosed per year, denoted annual incidence, of CD is 12-20 per 100,000 persons in Europe and North America. The numbers are 6 and 5 per 100,000 persons, respectively for Asia and the Middle East. New Zealand and Australia have the highest incidence figures, calculated to 27 and 50 per 100 000, respectively.
CD affects any part of the gastrointestinal tract, from mouth to anus, although in the majority of the cases the disease starts in the distal small bowel. CD involves the whole bowel wall (transmural inflammation). UC is restricted to inflammation in the colon and involves only the mucosa. UC has somewhat higher incidence figures than CD. There is a relationship between UC and CD by the fact that for about 15% of patients with colonic inflammation the diagnoses cannot be histopathologically distinguished. These patients are classified as having Indeterminate Colitis.
Common symptoms associated with IBD are abdominal pain, vomiting, diarrhoea, rectal bleeding, weight loss and cramps or spams in the lower abdomen. In severe cases the tendency to develop intra-abdominal fistulas gives rise to deep infections. Longstanding inflammation may lead to intestinal strictures. Surgical treatment usually involves percutaneous drainage of deep abscesses followed by surgery with resection of diseased bowel segments. Diagnosis is generally assessed by inflammatory markers in blood and stool, followed by ileo-colonoscopy with biopsies of pathological lesions.
First hand medical treatment consists of antibiotics and anti-inflammatory medication. There are several anti-inflammatory drugs, of which cortisone, azathioprine and antibodies against TNF are the most frequently used. Even if a positive response is seen both short- and long-term, these medications often lead to adverse reactions and patients often need to reduce the dose to a minimum or taper them out completely.
Both CD and UC as inflammatory disorders have long been considered as a breakdown in immunoregulation in the tissues of the intestinal mucosa, representing the most immunologically active sites of the human body. The interaction between luminal flora and the adaptive immune system is considered critical to disease pathogenesis. T-cells are central to cell-mediated adaptive immunity. Two main subdivisions of T-cells may be defined, were T-effector cells (Teffs) can be generalised to represent proinflammatory activities, and Tregs to represent an anti-inflammatory check. Exuberant Teff activity is observable in both animal models and human disease alike, and has been attributed in recent years to a breakdown in Treg-mediated homoeostatic mechanisms. However, it remains difficult to attribute IBD immunopathogenesis to any specific functional or numerical defect in Tregs themselves. This is in no small part due to the fact that proposed in vivo mechanisms of Treg function in humans remain largely speculative. Regardless, numerous animal models and early clinical experiences have suggested that Treg cells could be harnessed for treatment of a range of inflammatory disorders, and particularly IBD.
T-cells impart control locally; individually influencing control of immune responses over relatively short distances. Consequently, the migration of T-cells between intestinal mucosa and other bodily compartments is a critical determinant of functional responses. Several large-scale clinical trials have focused on blocking Teff migration to intestinal tissues through pharmaceutical blockade of either adhesion molecules or chemoattractants critical of T-cell migration to intestinal mucosa, with mixed success.
A majority of the knowledge around the T-cell pathology of IBD is inferred from mouse models. It is well established that transfer of nave conventional CD4+ T-cells into immune deficient mice results in a reaction against intestinal flora and establishment of intestinal inflammation, which can be rescued by co-transfer of Treg populations. It is also clear that Treg transfer into mice can resolve established intestinal inflammation. In the human setting, early indications of the correlation between intestinal tolerance and the human autoimmune syndrome were linked with FOXP3 mutations, the most common manifestation of which is chronic intestinal inflammation.
An accumulating body of data in patients with active and inactive IBD, and under various treatments, has yielded disparate results. Early studies suggested that the (lamina propria) LP of both CD and ulcerative colitis (UC) patients contained functional Tregs. Some studies have reported increased levels of Tregs in inflamed LP of IBD patients.
Considering the importance of migration of cells between the periphery and mucosal tissues, it is critical to consider the peripheral Treg pool in relation to direct observations of the inflamed mucosa. Several early studies have reported decreased levels of peripheral CD4+ Treg cells in patients with active intestinal inflammation. However, the opposite has also been observed, with an increased frequency of peripheral CD4+ Tregs in IBD patients, though lower frequency is often observed in active when compared to inactive disease.
Studies investigating Treg response in IBD patients undergoing anti-tumour necrosis factor (anti-TNF) therapies have reported increased levels of peripheral Tregs, particularly among clinical responders. However, other studies have reported no change in peripheral Treg frequency, and even a decreased frequency. Similar studies in rheumatoid arthritis have shown that responders to anti-TNF and methotrexate therapies show increased numbers of peripheral Treg cells. Curiously, addition of anti-TNF drugs to activated T-cells from patients resulted in the generation of Treg cells in vitro.
In summary, while it may be generally anticipated that IBD is characterised by a breakdown of immunotolerance in the intestinal mucosa, there is a lack of consistent correlation with an impaired Treg function or diminished abundance in patient tissues. This may be a result of as yet crude analytical methods to identify Treg cells, discriminate Treg subsets, and to assay their functional properties. It is also likely a function of still incomplete understanding of Treg origin and function in intestinal immune homeostasis. Recent insights into T-cell immunity in the intestinal mucosa have come from more detailed studies of T-cell migration and induction in the periphery.
However, there is a need to identify Treg cells that are suitable for use in cellular immunotherapy for the treatment of inflammatory and autoimmune diseases, notably IBD.